Pulsed electric fields are produced in cardiac muscle by internal defibrillators and are commonly used for treatment of cardiac fibrillation. More effective use of the shock current will conserve energy and minimize tissue injury. However, strategies to achieve this goal are largely ad hoc. The efficacy of the defibrillation pulse is determined in large part by the excitation response of the cell to the pulse, and a better understanding of the biophysical basis for this response may lead to a rationale for future strategies. The goal of this basic science research is to further our understanding of the electrical response of cardiac muscle to the pulsed electric fields produced during electrical defibrillation and stimulation. Within this framework, I propose to focus on, and experimentally test three current, theoretical concepts (models) which describe different aspects of the excitatory process: 1) a new model which describes the active response of the cell membrane to external electric fields (Tung-Borderies model), 2) the secondary source model which may account for cardiac excitation in regions remote from the stimulus electrodes (Plonsey-Barr-Witkowski model), and 3) the anisotropic bidomain model which may account for cardiac excitation in regions adjacent to the stimulus electrodes (Sepulveda-Roth-Wikswo model). This project will develop quantitative tests of these concepts at the cellular and multicellular levels by experimental measurements of transmembrane potential, using the whole cell patch clamp technique and voltage-sensitive indicator dyes (techniques already in use in my laboratory). Such knowledge could prove to be helpful in the evaluation of the overall therapeutic value of shock pulses used for excitation of both normal and diseased heart. A systems approach will be used in which experiment will proceed in a complementary fashion to the theoretical models to test the predictions of the models. Biomathematical techniques including model simulation and instrumentation development will complement the experimental measurements. Together, these approaches may help to clarify some of the basic aspects of cardiac excitation--in particular, the evolution of temporal and spatial patterns of transmembrane potential in the cell and in the tissue during field stimulation.